Combination of azelastine and steroids

ABSTRACT

A pharmaceutical product or formulation, which comprises azelastine or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and a steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, preferably the product or formulation being in a form suitable for nasal or ocular administration.

This application is a §371 National Stage Application of InternationalApplication No. PCT/GB03/02557, filed on 13 Jun. 2003, claiming thepriority of Great Britain Patent Application No. 0213739.6 filed on 14Jun. 2002, the entire disclosures of which are herein incorporated byreference in their entirety.

The present invention relates to pharmaceutical products andformulations. More particularly the present invention relates topharmaceutical products and formulations useful for preventing orminimising allergic reactions. More particularly, but not exclusively,the present invention relates to pharmaceutical products andformulations for nasal and ocular use.

Such allergic reactions commonly comprise the allergy-related andvasomotor-related symptoms and the rhinovirus-related symptoms.

It is known to use antihistamines in nasal sprays and eye drops to treatallergy-related conditions. Thus, for example, it is known to use theantihistamine azelastine (usually as the hydrochloride salt) as a nasalspray against seasonal or perennial allergic rhinitis, or as eye dropsagainst seasonal and perennial allergic conjunctivitis.

It is also known to treat these conditions using a corticosteroid, whichwill suppress nasal and ocular inflammatory conditions. Among thecorticosteroids known for nasal use are, for example, beclomethasone,mometasone, fluticasone, budesonide and cyclosenide. Corticosteroidsknown for ocular anti-inflammatory use include betamethasone sodium,dexamethasone sodium and prednisolone acetate, for example.

It would be highly desirable, however, to provide a treatment thatcombines the effects of anti-histamine treatments and steroidtreatments, in a pharmaceutically acceptable formulation, which istolerated in situ, without significantly disrupting the potency of theconstituent pharmaceuticals.

We have now found that, very surprisingly, azelastine(4-[(4-Chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthalazinone),or a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof, preferably in salt form and even morepreferably in the form of the hydrochloride salt, can advantageously becombined with a steroid, or a pharmaceutically acceptable salt, solvateor physiologically functional derivative thereof, to provide a stable,very effective combination product or formulation preferably for nasalor ocular treatment. The combination can provide, in a singleadministration or dosing regime, the antihistaminic properties ofazelastine and the anti-inflammatory (and/or other) properties of thesteroid, without any significant interference between the two, oradverse reaction in situ.

In one aspect the invention provides a pharmaceutical formulationcomprising azelastine or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof and a steroid, preferablya corticosteroid, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof the formulation preferablybeing in a form suitable for administration nasally or ocularly. In anembodiment, the formulation contains the steroid in an amount from about50 micrograms/ml to about 5 mg/ml of the formulation. In an embodiment,the formulation contains a suspension containing 0.0005% to 2%(weight/weight of the formulation) of azelastine or a pharmaceuticallyacceptable salt of azelastine, and from 0.0357% (weight/weight of theformulation), alternatively from 0.5%, to 1.5% (weight/weight of theformulation) of said steroid. In an embodiment, the formulation containsa suspension containing from 0.001% to 1% (weight/weight of theformulation) azelastine, or salt thereof, and from 0.0357%(weight/weight of the formulation), alternatively from 0.5%, to 1.5%(weight/weight of the formulation) steroid.

The term “physiologically functional derivative” as used herein denotesa chemical derivative of any of the specific therapeutic agentsdescribed herein having the same or similar physiological function asthe free base therapeutic agent and, for example, being convertible inthe body thereto. According to the present invention, examples ofphysiologically functional derivatives include esters.

The preferred forms of formulations of the invention are nasal drops,eye drops, nasal sprays, nasal inhalation solutions or aerosols orinsufflation powders.

Preferred embodiments of the invention can comprise stable aqueoussolutions of azelastine or one or more of its salts, in combination withsteroids which may be beclomethasone, mometasone, fluticasone,budesonide or cyclosenide, which can be used in the form of inhalationsolution, pressurized aerosol, eye drops or nasal drops, and in aparticular preferred embodiment, in the form of a spray (preferably anasal spray). The spray can, for example, be formed by the use of aconventional spray-squeeze bottle or a pump vaporizer. In addition, itis also possible to use compressed gas aerosols. In a preferredembodiment, 0.03 to 3 mg of azelastine base and 0.05 to 0.15 mg of thesteroid should be released per individual actuation.

The formulations preferably contain a preservative and/or stabilizer.These include, for example: ethylene diamine tetra-acetic acid (edeticacid) and its alkali salts (for example dialkali salts such as disodiumsalt, calcium salt, calcium-sodium salt), lower alkylp-hydroxybenzoates, chlorhexidine (for example in the form of theacetate or gluconate) and phenyl mercury borate. Other suitablepreservatives are: pharmaceutically useful quaternary ammoniumcompounds, for example cetylpyridinium chloride, tetradecyltrimethylammonium bromide, generally known as “cetrimide”,benzyldimethyl-[2-[2-[p-(1,1,3,3-tetramethyl-butyl)phenoxy]ethoxy]-ammoniumchloride, generally known as “benzethonium chloride” and myristylpicolinium chloride. Each of these compounds may be used in aconcentration of 0.002 to 0.05%, for example 0.02% (weight/volume inliquid formulations, otherwise weight/weight). Preferred preservativesamong the quaternary ammonium compounds are, however, alkylbenzyldimethyl ammonium chloride and mixtures thereof for example thecompounds generally known as “benzalkonium chloride”.

The total amount of preservatives in the formulations (solutions,ointments, etc.) is preferably from 0.001 to 0.10 g, preferably 0.01 gper 100 ml of solution/suspension or 100 g of formulation.

In the case of preservatives, the following amounts of individualsubstances can, for example, be used: thimero sal 0.002-0.02%;benzalkonium chloride 0.002 to 0.02% (in combination with thimero salthe amount of thimero sal is, for example=0.002 to 0.005%;);chlorhexidine acetate or gluconate 0.01 to 0.02%; phenylmercuric/nitrate, borate, acetate 0.002-0.004%; p-hydroxybenzoic acidester (for example, a mixture of the methyl ester and propyl ester inthe ratio 7:3): preferably 0.05-0.15, more preferably 0.1%.

The preservative used is preferably a combination of edetic acid (forexample, as the disodium salt) and benzalkonium chloride. In thiscombination, the edetic acid is preferably used in a concentration of0.05 to 0.1%, benzalkonium chloride preferably being used in aconcentration of 0.005 to 0.05%, more preferably 0.01%.

In the case of solutions/suspensions reference is always made to percentby weight/volume, in the case of solid or semi-solid formulations topercent by weight/weight of the formulation.

Further auxiliary substances which may, for example, be used for theformulations of the invention are: polyvinyl pyrrolidone, sorbitan fattyacid esters such as sorbitan trioleate, polyethoxylated sorbitan fattyacid esters (for example polyethoxylated sorbitan trioleate),sorbimacrogol oleate, synthetic amphotensides (tritons), ethylene oxideethers of octylphenolformaldehyde condensation products, phosphatidessuch as lecithin, polyethoxylated fats, polyethoxylatedoleotriglycerides and polyethoxylated fatty alcohols. In this context,polyethoxylated means that the relevant substances containpolyoxyethylene chains, the degree of polymerisation of which isgenerally between 2 to 40, in particular between 10 to 20. Thesesubstances are preferably used to improve the solubility of theazelastine component.

It is optionally possible to use additional isotonization agents.Isotonization agents which may, for example, be used are: saccharose,glucose, glycerine, sorbitol, 1,2-propylene glycol and NaCl.

The isotonization agents adjust the osmotic pressure of the formulationsto the same osmotic pressure as nasal secretion For this purpose thesesubstances are in each case to be used in such amount that, for example,in the case of a solution, a reduction in the freezing point of 0.50 to0.56 degree C. is attained in comparison to pure water.

In Example 1, it is possible to use instead of NaCl per 100 ml ofsolution, for example: Glucose 1H₂O 3.81 g; saccharose 6.35 g; glycerine2.2 g; 1,2-propylene glycol 1.617 g; sorbitol 3.84 g (in the case ofmixtures of these substances correspondingly less may optionally beused).

Moreover, it is possible to add thickening agents to solutions accordingto the present invention to prevent the solution from flowing out of thenose too quickly and to give the solution a viscosity of about 1.5 to 3,preferably 2 mPa.

Such thickening agents may, for example, be: cellulose derivatives (forexample cellulose ether) in which the cellulose-hydroxy groups arepartially etherified with lower unsaturated aliphatic alcohols and/orlower unsaturated aliphatic oxyalcohols (for example methyl cellulose,carboxymethyl cellulose, hydroxypropyhnethylcellulose), gelatin,polyvinylpyrrolidone, tragacanth, ethoxose (water soluble binding andthickening agents on the basis of ethyl cellulose), alginic acid,polyvinyl alcohol, polyacrylic acid, pectin and equivalent agents.Should these substances contain acid groups, the correspondingphysiologically acceptable salts may also be used.

In the event of the use of hydroxypropyl cellulose, 0.1% by weight ofthe formulation, for example, is used for this purpose.

In the event of the use of Avicel RC 591 or CL 611, microcrystallinecellulose and carboxymethyl cellulose sodium commercially available fromFMC BioPolymer, 0.65-3.0% by weight of the formulation, for example, isused for the purpose.

It is also possible to add to the formulations buffer substances such ascitric acid/sodium hydrogensulphate borate buffer, phosphates (sodiumhydrogenorthophosphate, disodium hydrogenphosphate), trometamol orequivalent conventional buffers in order, for example, to adjust theformulations to a pH value of 3 to 7, preferably 4.5 to 6.5.

The amount of citric acid is, for example, 0.01 to 0.14 g, preferably0.04 to 0.05 g, the amount of disodium hydrogenphosphate 0.1 to 0.5 g,preferably 0.2 to 0.3 g per 100 ml of solution. The weights given relatein each case to the anhydrous substances.

In the case of solutions and suspensions, the maximum totalconcentration of active agent and buffer is preferably less than 5%, inparticular less than 2% (weight/volume).

For the nasal application, a solution or suspension can preferably beused which is applied as an aerosol, i.e. in the form of a finedispersion in air or in another conventional carrier gas, for example bymeans of a conventional pump vaporizer.

Application as a dosage aerosol is, however, also possible. Dosageaerosols are defined as being pressure packings which contain theazelastine or its salts in combination with steroid, in the form of asolution or suspension in a so-called propellant. The propellant may bea pressurized liquid chlorinated, fluorinated hydrocarbon or mixtures ofvarious chlorinated, fluorinated hydrocarbons as well as propane,butane, isobutene or mixtures of these among themselves or withchlorinated, fluorinated hydrocarbons which are gaseous at atmosphericpressure and room temperature. Hydrofluorocarbons (HFCs), such as HFC134a, and HFC 227a can also be used, and are preferred for environmentalreasons. The pressure packing has a dosage or metering valve which, onactuation, releases a defined amount of the solution or suspension ofthe medicament. The subsequent very sudden vaporization of thepropellant tears the solution or suspension of azelastine into thefinest droplets or minute particles which can be sprayed in the nose orwhich are available for inspiration into the nose. Certain plasticapplicators may be used to actuate the valve and to convey the sprayedsuspension into the nose.

In the case of application as an aerosol, it is also possible to use aconventional adapter.

Particularly preferred embodiments of the present invention arehereinafter described and it will of course be appreciated that any ofthe previous description of suitable ingredients and formulationcharacteristics can also be applicable to the following products andformulations as provided by the present invention.

It will be appreciated, therefore, that the present invention furtherprovides a pharmaceutical product comprising (i) azelastine, or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof, provided in an aerosol formulation preferablytogether with a propellant typically suitable for MDI delivery, and (ii)at least one steroid, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, provided in an aerosolformulation preferably together with a propellant typically suitable forMDI delivery, as a combined preparation for simultaneous, separate orsequential use in the treatment of conditions for which administrationof one or more anti-histamine and/or one or more steroid is indicated.

The present invention also provides an aerosol formulation preferablysuitable for MDI delivery comprising (i) azelastine, or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof and (ii) at least one steroid, or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof, together with a propellant.

It will also be appreciated from the above, that the respectivetherapeutic agents of the combined preparation can be administeredsimultaneously, either in the same or different pharmaceuticalformulations, or separately or sequentially. If there is separate orsequential administration, it will also be appreciated that thesubsequently administered therapeutic agents should be administered to apatient within a time scale so as to achieve, or more particularlyoptimise, the above referred to advantageous synergistic therapeuticeffect of a combined preparation as present in a pharmaceutical productaccording to the present invention.

Suitable propellants for use in pharmaceutical products of formulationsas provided by the present invention include 1,1,1,2-tetrafluoroethane(HFA 134a) or 1,1,1,2,3,3,3,-heptafluoropropane (HFA 227), or acombination of both, or mono-fluoro trichloromethane and dichlorodifluoromethane, in particular 1,1,1,2-tetrafluoroethane (HFA 134a) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227), with HFA 134a beingpreferred.

A pharmaceutical aerosol formulation according to the present inventionpreferably further comprises a polar cosolvent such as C₂₋₆ aliphaticalcohols and polyols, for example ethanol, isopropanol and propyleneglycol, with ethanol often being preferred. Preferably, theconcentration of the cosolvent is in the range of about 2 to 10% byweight, typically up to about 5%, of the total formulation.

A pharmaceutical aerosol formulation according to the present inventionmay further comprise one or more surfactants. Such surfactants can beincluded to stabilise the formulations and for lubrication of a valvesystem. Some of the most commonly used surfactants in aerosolformulations are oils derived from natural sources, such as corn oil,olive oil, cottonseed oil and sunflower seed oil, and alsophospholipids. Suitable surfactants can include lecithin, oleic acid orsorbitan oleate. In an embodiment, the formulation contains from about50 micrograms to about 1 milligram of surfactant per ml of theformulation.

A further preferred embodiment of the present invention can be where aformulation or product is provided in the form of insufflatable powder,where preferably the maximum particle size of the substance suitablydoes not exceed 10 μm. Azelastine or its salts and the steroid may bemixed with inert carrier substances or drawn up onto inert carriersubstances. Carrier substances which may, for example, be used are:sugars such as glucose, saccharose, lactose and fructose. Also starchesor starch derivatives, oligosaccharides such as dextrins, cyclodextrinsand their derivatives, polyvinylpyrrolidone, alginic acid, tylose,silicic acid, cellulose, cellulose derivatives (for example celluloseether), sugar alcohols such as mannitol or sorbitol, calcium carbonate,calcium phosphate, etc.

In one embodiment, the therapeutic agents employed have a particle sizeof less than about 10 μm, preferably less than 5 μm.

The use of insufflation powders can represent a preferred embodiment ofthe present invention and there is provided by the present invention apharmaceutical product comprising (i) azelastine, or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof, provided as an insufflation powder, and (ii) at least onesteroid, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, provided as aninsufflation powder, as a combined preparation for simultaneous,separate or sequential use in the treatment of conditions for whichadministration of one or more anti-histamine and/or one or more steroidis indicated.

It will be appreciated from the above, that the respective therapeuticagents of the combined preparation can be administered simultaneously,either in the same or different insufflation powder formulations, orseparately or sequentially. If there is separate or sequentialadministration as discussed above, it will also be appreciated that thesubsequently administered therapeutic agents should be administered to apatient within a time scale so as to achieve, or more particularlyoptimise, the above referred to advantageous synergistic therapeuticeffect of a combined preparation as present in a pharmaceutical productaccording to the present invention.

The present invention also provides an insufflation powder formulationcomprising (i) azelastine, or a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof, and (ii) atleast one steroid, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, together with apharmaceutically acceptable carrier or excipient therefor.

Dry insufflation powder formulations as provided by the presentinvention can be beneficial where it is required that therapeutic agentsas employed according to the present invention are retained in the nasalcavity, and systemic side effects can be minimised or eliminated.Furthermore, insufflation powder formulations as employed in the presentinvention can be beneficial whereby retention of azelastine, or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof, at the nasal mucosa is improved, and the bitteraftertaste associated with liquid antihistamine formulationssignificantly reduced, whilst also exhibiting the synergistictherapeutic effect associated with the azelastine/steroid combinationsprovided by the present invention. By providing a dry insufflationpowder formulation of azelastine, together with a steroid, having anaverage particle size of less than about 10 μm, the therapeutic agentscan be restricted primarily to the desired target organ, the nasalmucosa.

A dry powder insufflation formulation according to the present inventioncan be administered by the use of an insufflator, which can produce afinely divided cloud of the dry powder. The insufflator preferably isprovided with means to ensure administration of a substantiallypre-determined amount of a formulation or product as provided by thepresent invention The powder may be used directly with an insufflatorwhich is provided with a bottle or container for the powder, or thepowder may be filled into a capsule or cartridge, such as a gelatincapsule, or other single dose device adapted for administration. Theinsufflator preferably has means to open the capsule or other dosedevice.

Preferred combinations of therapeutic agents employed in pharmaceuticalproducts and formulations according to the present invention (inparticular nasal sprays or drops, aerosol or insulation products andformulations as described above) comprise any one of the followingcombinations.

The present invention further provides, therefore, a pharmaceuticalproduct comprising (i) azelastine, or a pharmaceutically acceptable saltthereof, and (ii) at least one steroid selected from the groupconsisting of beclomethasone, fluticasone, mometasone andpharmaceutically acceptable esters thereof, as a combined preparationfor simultaneous, separate or sequential use in the treatment ofconditions for which administration of one or more anti-histamine and/orone or more steroid is indicated Suitably the esters can be selectedfrom beclomethasone dipropionate, fluticasone propionate, fluticasonevalerate, mometasone furoate and mometasone furoate monohydrate.

The present invention also provides a pharmaceutical formulationcomprising (i) azelastine, or a pharmaceutically acceptable saltthereof, and (ii) at least one steroid selected from the groupconsisting of beclomethasone, fluticasone, mometasone andpharmaceutically acceptable esters thereof together with apharmaceutically acceptable carrier or excipient therefor. Suitably theesters can be selected from beclomethasone dipropionate, fluticasonepropionate, fluticasone valerate, mometasone furoate and mometasonefuroate monohydrate.

In the case of a nasal spray, a particularly preferred formulation asprovided by the present invention is a nasal spray comprisingazelastine, or a pharmaceutically acceptable salt thereof (preferablyazelastine hydrochloride), together with mometasone either as the freebase or in ester form, preferably as mometasone furoate.

Specific combinations of therapeutic agents employed in pharmaceuticalproducts and formulations according to the present invention compriseany one of the following combinations:

-   -   azelastine hydrochloride and beclomethasone dipropionate;    -   azelastine hydrochloride and fluticasone propionate;    -   azelastine hydrochloride and fluticasone valerate;    -   azelastine hydrochloride and mometasone furoate; and    -   azelastine hydrochloride and mometasone furoate monohydrate.

There is also provided by the present invention a method for theprophylaxis or treatment in a mammal, such as a human, of conditions forwhich administration of one or more anti-histamine and/or one or moresteroid is indicated, which method comprises administration of atherapeutically effective amount of a pharmaceutical productsubstantially as hereinbefore described, as a combined preparation forsimultaneous, separate or sequential use in the treatment of suchconditions.

The present invention also provides a method for the prophylaxis ortreatment in a mammal, such as a human, of conditions for whichadministration of one or more anti-histamine and/or one or more steroidis indicated, which method comprises administration of a therapeuticallyeffective amount of a pharmaceutical formulation substantially ashereinbefore described.

There is also provided by the present invention for use in themanufacture of a medicament for the prophylaxis or treatment in amammal, such as a human, of conditions for which administration of oneor more anti-histamine and/or one or more steroid is indicated, apharmaceutical product, as a combined preparation for simultaneous,separate or sequential use in the treatment of such conditions.

There is further provided by the present invention, therefore, a processof preparing a pharmaceutical product substantially as hereinbeforedescribed, which process comprises providing as a combined preparationfor simultaneous, separate or sequential use in the treatment ofconditions for which administration of one or more anti-histamine and/orone or more steroid is indicated: (i) azelastine, or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof, and (ii) at least one steroid, or a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof.

The present invention also provides a process of preparing apharmaceutical formulation substantially as hereinbefore described,which process comprises admixing a pharmaceutically acceptable carrieror excipient with: (i) azelastine, or a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof, and (ii)at least one steroid, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof Preferably pharmaceuticalformulations according to the present invention can compriseinsufflation powder formulations, nasal sprays, nasal inhalationsolutions or aerosols substantially as hereinbefore described.

The present invention is now illustrated by the following Examples,which do not limit the scope of the invention in any way. In Exampleswhere only the ingredients of formulations according to the presentinvention are listed, these formulations are prepared by techniques wellknown in the art.

EXAMPLE 1 Nasal Spray or Nasal Drops with 0.1% Azelastine Hydrochlorideas Active Ingredient and Steroid 0.1%

Quantity Sr. No Ingredients % w/v 1. Azelastine hydrochloride 0.1% 2.Steroid 0.1% 3. Disodium edetate 0.005% 4. Sodium chloride 0.9% 5.Benzalkonium chloride 0.001% 6. Avicel RC 591 1.2% 7. Citric acidmonohydrate 0.2% 8. Disodium hydrogen 0.1% phosphate dodecahydrate 9.Purified water

EXAMPLE 2

Dosage aerosol giving off 0.5 mg of azelastine hydrochloride and 50micrograms of beclomethasone dipropionate freon solvate per stroke.

About 8.0 kg of a mixture of 70 parts by weight ofdifluorodichloromethane and 30 parts by weight of1,2dichlorotetrafluoroethane are cooled to about −55 degree C. in anappropriate cooling vessel. A mixture of 0.086 kg of pre-cooledsorbitantrioleate and 0.8600 kg of pre-cooled trichlorofluoromethane aredissolved with stirring into the mixture at −55 degrees C., 0.0688 kg ofmicronized azelastine hydrochloride, 0.00688 kg of beclomethasonedipropionate freon solvate and 0.0688 kg of micronized lactose are thenincorporated in portions into the solution thereby obtained withintensive stirring. The total weight of the suspension thereby obtainedis made up to 9.547 kg through addition of more of the mixture of 70parts by weight of difluorodichloromethane and 30 parts by weight of1,2-dichlorotetrafluoroethane cooled to about −55 degree C.

Following closure of the cooling vessel the suspension is again cooledto about −55 degrees C. under intensive stirring. It is then ready to befilled.

EXAMPLE 3 Nasal Spray or Nasal Drops with Azelastine and Steroid*

Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride 0.10Fluticasone propionate 0.0357 Glycerin 2.60 Avicel RC 591 1.35Polysorbate 80 0.025 Benzalkonium chloride 0.01 Phenyl ethyl alcohol0.25 Purified water q.s. *Each spray delivers Azelastine Hydrochloride(140 mcg) and Fluticasone propionate (50 mcg).

EXAMPLE 4 Nasal Spray or Nasal Drops with Azelastine and Steroid*

Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride 0.10Fluticasone valerate 0.0357 Glycerin 2.60 Avicel RC 591 1.20 Polysorbate80 0.030 Benzalkonium chloride 0.01 Phenyl ethyl alcohol 0.25 Purifiedwater q.s. *Each spray delivers Azelastine Hydrochloride (140 mcg) andFluticasone valerate (50 mcg).

EXAMPLE 5 Nasal Spray or Nasal Drops with Azelastine and Steroid*

Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride 0.10Fluticasone propionate 0.0714 Glycerin 2.60 Avicel RC 581 1.35Polysorbate 80 0.025 Benzalkonium chloride 0.01 Phenyl ethyl alcohol0.25 Purified water q.s. *Each spray delivers Azelastine Hydrochloride(140 mcg) and Fluticasone propionate (50 mcg).

EXAMPLE 6 Nasal Spray or Nasal Drops with Azelastine and Steroid

Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride 0.10Mometasone Furoate 0.05173 Glycerin 2.30 Disodium edetate 0.005Polysorbate 80 0.0125 Avicel RC 581 1.35 Benzalkonium chloride 0.01Citric acid monohydrate 0.20 Disodium hydrogen phosphate 0.10dodecahydrate Purified water q.s.

EXAMPLE 7 Nasal Spray or Nasal Drops with Azelastine and Steroid*

Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride 0.10Mometasone Furoate 0.05173 monohydrate Glycerin 2.60 Avicel CL 611 2.295Polysorbate 80 0.0125 Benzalkonium chloride 0.01 Phenyl ethyl alcohol0.25 Purified water q.s. *Each spray delivers Azelastine Hydrochloride(140 mcg) and Mometasone furoate (50 mcg).

EXAMPLE 8 Nasal MDI with Azelastine and Steroid

Sr. No. Ingredients Quantity in mcg Azelastine Hydrochloride 140Mometasone Furoate 50 monohydrate HFA 134a q.s. Lecithin 0.1% Alcohol(up to 5%)

EXAMPLE 9 Nasal MDI with Azelastine and Steroid

Sr. No. Ingredients Quantity in mcg Azelastine Hydrochloride 140Fluticasone propionate 50 HFA 134a q.s. Sorbitan trioleate 0.1% Alcohol(up to 5%)

EXAMPLE 10 Nasal MDI with Azelastine and Steroid

Sr. No. Ingredients Quantity in mcg Azelastine Hydrochloride 140Fluticasone propionate 100 HFA 134a q.s. Oleic acid 0.1%

EXAMPLE 11 Nasal MDI with Azelastine and Steroid

Sr. No. Ingredients Quantity in mcg Azelastine Hydrochloride 140Fluticasone Valerate 50 HFA 134a q.s. Alcohol (up to 5%)Insufflatable Powders Containing Azelastine and Steroid:

Sr. No. Ingredients Quantity (% w/w) Azelastine 140 mcg Hydrochloride(Micronized) Fluticasone propionate  50 mcg Lactose q.s. (up to 25 mcg)

Sr. No. Ingredients Quantity (% w/w) Azelastine 140 mcg Hydrochloride(Micronized) Fluticasone propionate 100 mcg Mannitol q.s. (up to 30 mcg)

Sr. No. Ingredients Quantity (% w/w) Azelastine 140 mcg Hydrochloride(Micronized) Fluticasone propionate 250 mcg Lactose q.s. (up to 30 mcg)

1. A pharmaceutical formulation comprising: azelastine, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable ester of fluticasone, wherein said pharmaceutical formulationis in a dosage form suitable for nasal administration.
 2. Thepharmaceutical formulation of claim 1, wherein said pharmaceuticallyacceptable salt of azelastine is azelastine hydrochloride.
 3. Thepharmaceutical formulation of claim 1, wherein said pharmaceuticallyacceptable ester of fluticasone is fluticasone propionate or fluticasonevalerate.
 4. The pharmaceutical formulation of claim 1, wherein saidformulation has a particle size of less than 10 μm.
 5. Thepharmaceutical formulation of claim 1, wherein said formulation is anaqueous suspension comprising from 0.0005% (weight/weight) to 2%(weight/weight) of said azelastine, or said pharmaceutically acceptablesalt thereof, and from 0.0357% (weight/weight) to 1.5% (weight/weight)of said pharmaceutically acceptable ester of fluticasone.
 6. Thepharmaceutical formulation according to claim 5, comprising from 0.001%(weight/weight) to 1% (weight/weight) of said azelastine, or saidpharmaceutically acceptable salt thereof, and from 0.0357%(weight/weight) to 1.5% (weight/weight) of said pharmaceuticallyacceptable ester of fluticasone.
 7. The pharmaceutical formulation ofclaim 1, further comprising at least one additive selected from thegroup consisting of a buffer, a preservative, a suspending agent athickening agent, a surfactant, an isotonic agent and combinationsthereof.
 8. The pharmaceutical formulation of claim 7, wherein saidsurfactant comprises a polysorbate, poloxamer or combinations thereof.9. The pharmaceutical formulation of claim 7, wherein said isotonicagent comprises sodium chloride, saccharose, glucose, glycerine,sorbitol, 1,2-propylene glycol or combinations thereof.
 10. Thepharmaceutical formulation of claim 7, wherein said preservativecomprises edetic acid or its alkali salts, lower alkylp-hydroxybenzoates, chlorhexidine, phenyl mercury borate, or benzoicacid or a salt thereof, a quaternary ammonium compound, sorbic acid or asalt thereof, or combinations thereof.
 11. The pharmaceuticalformulation of claim 7, wherein said suspending agent or said thickeningagent comprises cellulose derivatives, gelatin, polyvinylpyrrolidone,tragacanth, alginic acid, polyvinyl alcohol, polyacrylic acid, pectin,or combinations thereof.
 12. The pharmaceutical formulation of claim 1,which is an aqueous suspension.
 13. The pharmaceutical formulation ofclaim 1, wherein said dosage form suitable for nasal administrationcomprises nasal drops or a nasal spray.
 14. The pharmaceuticalformulation of claim 1, wherein said dosage form suitable for nasaladministration comprises nasal drops.
 15. The pharmaceutical formulationof claim 1, wherein said dosage form suitable for nasal administrationcomprises a nasal spray.
 16. The pharmaceutical formulation of claim 1,wherein said formulation is used in the treatment of conditions forwhich administration of one or more anti-histamine and/or one or moresteroid is indicated.
 17. The pharmaceutical formulation of claim 1,wherein said pharmaceutically acceptable salt of azelastine isazelastine hydrochloride and said pharmaceutically acceptable ester offluticasone is fluticasone propionate, and wherein said formulation isused in the treatment of conditions for which administration of one ormore anti-histamine and/or one or more steroid is indicated.
 18. Thepharmaceutical formulation of claim 1, wherein said pharmaceuticallyacceptable salt of azelastine is azelastine hydrochloride and saidpharmaceutically acceptable ester of fluticasone is fluticasonepropionate, and wherein said formulation further comprises apharmaceutically acceptable carrier or excipient therefor.
 19. Thepharmaceutical formulation of claim 1, wherein said pharmaceuticallyacceptable salt of azelastine is azelastine hydrochloride and saidpharmaceutically acceptable ester of fluticasone is fluticasonevalerate, and wherein said formulation is used in the treatment ofconditions for which administration of one or more anti-histamine and/orone or more steroid is indicated.
 20. The pharmaceutical formulation ofclaim 1, wherein said pharmaceutically acceptable salt of azelastine isazelastine hydrochloride and said pharmaceutically acceptable ester offluticasone is fluticasone valerate, and wherein said formulationfurther comprises a pharmaceutically acceptable carrier or excipienttherefor.
 21. A process of preparing a pharmaceutical formulation ofclaim 1, which process comprises admixing a pharmaceutically acceptablecarrier or excipient with azelastine, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable ester of fluticasone.22. The pharmaceutical formulation of claim 1, wherein saidpharmaceutically acceptable ester of fluticasone is fluticasonepropionate.
 23. The pharmaceutical formulation of claim 1, wherein saidpharmaceutically acceptable ester of fluticasone is fluticasonevalerate.
 24. A pharmaceutical formulation comprising azelastinehydrochloride; and, fluticasone propionate, wherein said formulation isin the dosage form of as a nasal spray, and wherein said formulation isused in the treatment of conditions for which administration of one ormore anti-histamine and/or one or more steroid is indicated.
 25. A nasalspray formulation comprising (i) azelastine, or a pharmaceuticallyacceptable salt thereof, (ii) a pharmaceutically acceptable ester offluticasone, and (iii) a pharmaceutically acceptable carrier orexcipient therefor.
 26. The pharmaceutical formulation of claim 6,comprising 0.1% (weight/weight) of azelastine hydrochloride, and from0.0357% to 1.5% (weight/weight) of fluticasone propionate.
 27. Thepharmaceutical formulation of claim 6, comprising 0.1% (weight/weight)of azelastine hydrochloride, and from 0.0357% to 1.5% (weight/weight) offluticasone valerate.
 28. The pharmaceutical formulation of claim 6,wherein said dosage form suitable for nasal administration comprises anasal spray.
 29. The pharmaceutical formulation of claim 26, whereinsaid dosage form suitable for nasal administration comprises a nasalspray.
 30. The pharmaceutical formulation of claim 27, wherein saiddosage form suitable for nasal administration comprises a nasal spray.31. The pharmaceutical formulation of claim 28, wherein saidpharmaceutically acceptable salt of azelastine is azelastinehydrochloride and wherein said pharmaceutically acceptable ester offluticasone is fluticasone propionate.
 32. The pharmaceuticalformulation of claim 28, wherein said pharmaceutically acceptable saltof azelastine is azelastine hydrochloride and wherein saidpharmaceutically acceptable ester of fluticasone is fluticasonevalerate.
 33. The pharmaceutical formulation of claim 25, wherein saidpharmaceutically acceptable salt of azelastine is azelastinehydrochloride and wherein said pharmaceutically acceptable ester offluticasone is fluticasone propionate.
 34. The pharmaceuticalformulation of claim 25, wherein said pharmaceutically acceptable saltof azelastine is azelastine hydrochloride and wherein saidpharmaceutically acceptable ester of fluticasone is fluticasonevalerate.
 35. The pharmaceutical formulation of claim 5, wherein saidpharmaceutically acceptable salt of azelastine is azelastinehydrochloride.
 36. The pharmaceutical formulation of claim 6, whereinsaid pharmaceutically acceptable salt of azelastine is azelastinehydrochloride.
 37. The pharmaceutical formulation of claim 28, whereinsaid pharmaceutically acceptable salt of azelastine is azelastinehydrochloride.
 38. The pharmaceutical formulation of claim 8, whereinsaid surfactant comprises a polysorbate.
 39. The pharmaceuticalformulation of claim 9, wherein said isotonic agent comprises glycerine.40. The pharmaceutical formulation of claim 10, wherein saidpreservative comprises edetate disodium and benzalkonium chloride. 41.The pharmaceutical formulation of claim 11, wherein said suspendingagent or said thickening agent comprises cellulose derivatives.
 42. Thepharmaceutical formulation of claim 1, further comprising edetatedisodium, glycerine, a thickening agent comprising microcrystallinecellulose and sodium carboxy methyl cellulose, polysorbate 80,benzalkonium chloride, phenyl ethyl alcohol, and purified water.
 43. Thepharmaceutical formulation of claim 24, further comprising edetatedisodium, glycerine, a thickening agent comprising microcrystallinecellulose and sodium carboxy methyl cellulose, polysorbate 80,benzalkonium chloride, phenyl ethyl alcohol, and purified water.
 44. Thepharmaceutical formulation of claim 25, further comprising edetatedisodium, glycerine, a thickening agent comprising microcrystallinecellulose and sodium carboxy methyl cellulose, polysorbate 80,benzalkonium chloride, phenyl ethyl alcohol, and purified water.
 45. Thepharmaceutical formulation of claim 1, wherein said formulationcomprises a pH from 3 to
 7. 46. The pharmaceutical formulation of claim1, wherein said formulation comprises a pH from 4.5 to 6.5.
 47. Apharmaceutical formulation comprising from 0.001% (weight/weight) to 1%(weight/weight) of azelastine hydrochloride, and from 0.0357%(weight/weight) to 1.5% (weight/weight) of fluticasone propionate,wherein said pharmaceutical formulation is an aqueous suspensionsuitable for nasal administration.
 48. A pharmaceutical formulationcomprising 1% (weight/weight) of azelastine hydrochloride, and from0.0357% (weight/weight) to 1.5% (weight/weight) of fluticasonepropionate, wherein said pharmaceutical formulation is an aqueoussuspension suitable for nasal administration.